Monoxygenase systems

Tetraethyl and tetramethyl lead under oxidative dealkylation metabolize to the highly neurotoxic metabolites, triethyl and trimethyl lead, respectively. In the liver, the reaction is catalyzed by a cytochrome P-450 dependent monoxygenase system (Kimmel et al. 1977). Complete oxidation of alkyl lead to inorganic lead also occurs (Bolanowska 1968). 

Kimmel EC, Fish RH, Casida JE. 1977. Bioorganotin chemistry Metabolism of organotin compounds in microsomal monoxygenase systems and in mammals J Agric food Chem 25 1-9. 

Gelb, M. H., Heimbrook, D. C., Malkonen, P., and Sligar, S. G. Stereochemistry and deuterium isotope effects in camphor hydroxylation by the cytochrome P450cam monoxygenase system. Biochemistry 21, 370-377 (1982). 

Serabjit-Singh, C.J. Wolf, C.R. and Philpot, R.M. The rabbit pulmonary monoxygenase system Immunochemical and biochemical characterization of enzyme components. J Biol Chem 254 9901-9907, 1979. 

Lewis, D. F. V. Compact and the importance of frontier orbitals in toxicity mediated by the cytochrome P450 monoxygenase system. Toxicol. Modeling 1995,1, 85-97. 

Sligar, S. G. (1975) A kinetic and equilibrium description of camphor hydroxylation by the P450cam monoxygenase system. Ph.D. Thesis, University of Illinois. 

Cashman JR. Flavin-containing monoxygenase. In Ioannides C, ed. Enzyme Systems that Metabolise Drugs and Other Xenobiotics. Chichester John Wiley and Sons, 2002 67-93. 

Figure 18-19 The ammonia oxidation system of the bacterium Nitrosomonas. Oxidation of ammonium ion (as free NH3) according to Eq. 18-17 is catalyzed hy two enzymes. The location of ammonia monooxygenase (step a) is uncertain but hydroxylamine oxidoreductase (step b) is periplas-mic. The membrane components resemble complexes I, III, and IV of the mitochondrial respiratory chain (Fig. 18-5) and are assumed to have similar proton pumps. Solid green lines trace the flow of electrons in the energy-producing reactions. This includes flow of electrons to the ammonia monoxygenase. Complexes HI and IV pump protons out but complex I catalyzes reverse electron transport for a fraction of the electrons from hydroxylamine oxidoreductase to NAD+. Modified from Blaut and Gottschalk.315...

Oxidation is by far the most important Phase I metabolic reaction. One of the main enzyme systems involved in the oxidation of xenobiotics appears to be the so called mixed function oxidases or monooxygenases, which are found mainly in the smooth endoplasmic reticulum of the liver but also occur, to a lesser extent, in other tissues. These enzymes tend to be nonspecific, catalysing the metabolism of a wide variety of compounds (Table 9.2). Two common mixed function oxidase systems are the cytochrome P-450 (CYP-450) and the flavin monoxygenase (FMO) systems (Appendix 12). The overall oxidations of these systems take place in a series of oxidative and reductive steps, each step being catalysed by a specific enzyme. Many of these steps require the presence of molecular oxygen and either NADH or NADPH as co-enzymes. 

How general is this requirement for a co-reductant (e. g., CO or H2) in achieving difficult catalytic hydrocarbon oxidations by dioxygen Sen s work has provided two examples of catalytic systems that operate in this manner (i. e., as monoxygenase analogs) [40, 44]. There have been other recent publications on catalytic systems for the oxidation of hydrocarbons, including olefins and aro-... 

Isolated lettuce chloroplasts could epoxidize zeaxanthin in the presence of reduced pyridine nucleotides and oxygen and the process was stimulated by bovine serum albumin (which protected the epoxidase system from inhibition by fatty acids). Detailed study led to the conclusion that the epoxidase was an external monoxygenase and that the violaxanthin cycle (of which epoxidation of zeaxanthin is a part) was a trans-membrane system wherein de-epoxidation took place on the loculus side and epoxidation on the stroma side of the membrane. This arrangement requires migration of the carotenoids of the violaxanthin cycle across the membrane in a type of shuttle. The possible role of this cycle in some regulatory mechanism of photosynthesis at the membrane level was also discussed. 

The drug may be inactivated in the liver on its way to the systemic circulation. An example of this is the inactivation of glyceryl trinitrate by hepatic monoxygenase enzymes during the first pass metabolism. 

Abbreviations PAH, polycyclic aromatic hydrocarbon DE, diol epoxide PAHDE, polycyclic aromatic hydrocarbon diol epoxide PAHTC, polycyclic aromatic hydrocarbon triol carbocation TC, triol carbocation BaP, benzo[a]pyrene BeP, benzo[e]pyrene BA, benz[a]anthracene DBA, dibenz[a,h]anthracene BcPh, benzo[c)phenanthrene Ch, chrysene MCh, methylchrysene MBA, 7-methyl benz[a]anthracene DMBA, 7,12-dimethyl benz[a]anthracene EBA, 7-ethyl benz[a]anthracene DB(a,l)P, dibenzo[a,l]pyrene MSCR, mechanism-based structure-carcinogenicity relationship PMO, Perturbational molecular orbital method dA, deoxyadenosine dC, deoxycytosine dG, deoxyguanosine MOS, monoxygenase enzyme system EH, epoxide hydrolase enzyme system N2(G), exocyclic nitrogen of guanine C, electrophilic centre of PAHTC K, intercalation constant CD, circular dichroism LD, linear dichroism. 

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